Halogenated aromatic hydrocarbons constitute a broad class of compounds with varying structure and toxicity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypical structure, is the most toxic compound of this type. Theoretical, quantitative structure activity relationship (QSAR) and experimental studies focusing on polychlorinated biphenyls (PCBs) as models have established the importance of molecular polarizability and receptor to PCB separation distance in binding to the dioxin or Ah receptor. The work suggests a new stacking type model for the Ah receptor which has universal applicability to the range of binding-structures observed. Further theoretical and experimental studies suggested that Ah receptor binding is a necessary but not sufficient condition for toxicity and a second receptor must be proposed to account for the structural requirements of planarity and halogenation in toxicity, as opposed to induction. A protein binding model consistent with the structural requirements for toxicity has been identified. Molecular modeling work, competitive binding assays and several in vivo studies have demonstrated the importance of thyroxine binding proteins in toxicity and suggested that the high toxicity of TCDD is the expression of potent and persistent thyroid hormone activity. A molecular mechanism is proposed involving a two protein-receptor model in which the planar aromatic system controls the initial receptor binding and halogen substitutents control subsequent nuclear events. This mechanistic hypothesis is being further investigated for its relevance in dioxin toxicity as well as insight into the mechanism of thyroid hormone action.